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Treatment of Neurodegenerative Diseases Through Inhibition of HSP90

a technology of heat shock protein and neurodegenerative diseases, applied in the direction of biocide, anti-noxious agents, drug compositions, etc., can solve the problems of significant reduction in the robustness of cellular networks, unbalanced chaperone requirement and chaperone capacity, and aggregate reduction and subsequent plaque or tangle formation

Active Publication Date: 2009-12-03
THE ROCKEFELLER UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0015]In accordance with the present invention, treatment of neurodegenerative diseases is achieved using small molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-brain barrier. Thus, in accordance with the present invention, there is provided a method for treatment of neurodegenerative disease comprising the step of administering to an individual in need of such treatment an effective amount of a purine-scaffold compound that inhibits Hsp90, and that crosses the blood-brain barrier or is otherwise delivered to the brain.

Problems solved by technology

Secondly, cancer cells harbor mutated oncogenic proteins.
Second, pathogenic mutants (such as of APP or presenilins in AD or mtau in FTDP-17 or mutant androgen receptor in bulbar muscular atrophy) may require Hsp90 for correct folding and functioning, thus Hsp90 inhibition may lead to the elimination of these proteins and result in reduction of aggregates and consequent plaque or tangle formation.
In aged organisms, chaperone overload leads to a significant decrease in the robustness of cellular networks shifting their function towards a more stochastic behavior.
Unbalanced chaperone requirement and chaperone capacity helps the accumulation of misfolded and aggregated proteins especially in the nervous system, due to the very limited proliferation potential of neurons.
In addition, damaged signaling networks lose their original stringency, and irregular protein phosphorylation occurs.
Unfortunately, known Hsp90 inhibitors such as geldanamycin and 17AAG, its derivative in Phase I clinical trial for cancer, and the unrelated compound radicicol have significant limitations.
They are poorly soluble, difficult to formulate and do not cross the blood-brain barrier.

Method used

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  • Treatment of Neurodegenerative Diseases Through Inhibition of HSP90
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Examples

Experimental program
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example 1

[0074]Juvenile mice: Four-to six-week old nu / nu athymic female mice were obtained from the National Cancer Institute-Frederick Cancer Center and maintained in ventilated caging. Experiments were earned out under an Institutional Animal Care and Use Committee-approved protocol, and institutional guidelines for the proper and humane use of animals in research were followed. Before administration, a solution of PU24FC1 was prepared at desired concentration in 50 μL vehicle (PBS:DMSO:EtOH at 1:1:1 ratio). In experiments designed to define the short-term effects of PU24FC1 on tau phosphorylation, mice (2 per time point) were treated with 200 mg / kg PU24FC1 or with vehicle alone. At the time of sacrifice, brains were collected and immediately flash frozen. For protein analysis brains were homogenized in SDS lysis buffer (50 mM Tris pH 7.4, 2% SDS). For long-term administration studies, mice (n=5) were treated every other day for 30 days with the indicated doses of PU24FC1. Weight and behav...

example 2

[0078]Transgenic mice: Transgenic mice, JNPL3 line (59) overexpressing mutant human tau (P301L, 4R0N) were used in this study. Mice were heterozygous and on a mixed hybrid genetic background composed of C57BL / DBA2 / SW, as published in ref. 59. These mice develop NFTs in the basal telencephalon, diencephalon, brainstem, and spinal cord, with severe pathology accompanied by degeneration in the spinal cord leading to dystonia, paralysis, and death in mice >12 months in age. Nine month-old male JNPL3 mice (n=2) were treated intraperitoneally with PU-DZ8 or vehicle for 5 days. Mice were sacrificed 12 h after last treatment by cervical dislocation under anesthesia.

[0079]To further examine the effect of Hsp90 on tau phosphorylation, we used the JNPL3 line of mice expressing mutant (P301L) tau protein (59). Genetic analyses have linked mutations in the tau gene to FTDP-17 (60, 61). Over 20 distinct pathogenic mutations have been identified, with P301L as the most common mutation in tauophati...

example 3

[0081]JNPL3 female mice 6.5 months of age were treated for 30 days, 5 day / week, with the Hsp90 inhibitor PU-DZ8 (FIG. 5) or vehicle, or sacrificed for time zero, n=4 / group. Brains were divided in subcortical and cortical regions and processed using the Greenberg and Davies extraction protocol. (77) Sarkosyl soluble fractions (S1) were analyzed by WB for p35 and Hsp70, and for tau epitopes found abnormally hyperphosphorylated in AD brains such as: S202 and T205 recognized by AT8,T181 by AT270, T231 by AT180. These are putative cdk5 / p35 sites. Protein bands were normalized to Hsp90 and plotted as relative units. The results are shown in FIG. 8A and B. Since tauopathy, characterized by pathogenic phosphorylation of tau can be due to aberrant kinase activity, the hsp90 inhibitor is effective because it affects the expression of the p35 protein, an activator of cdk5 known to phosphorylate tau at pathogenic sites, and thus alleviates tau phosphorylation at these sites.

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Abstract

Treatment of neurodegenerative diseases is achieved using small molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-brain barrier or are other wise delivered to the brain.

Description

CLAIM FOR PRIORITY [0001]This application claims the priority benefit of U.S. Provisional Application No. 60 / 806,427, filed Jun. 30, 2006, which is incorporated herein by reference for all purposes.STATEMENT OF FEDERAL FUNDING [0002]This invention was supported in part by NIH grant AG09464. The United States government may have certain rights in this invention.BACKGROUND OF THE INVENTION [0003]This application relates to the treatment of neurodegenerative diseases through inhibition of heat shock protein 90 (HSP90).[0004]The HSP90 family of proteins has four recognized members in mammalian cells: Hsp90 α and β, Grp94 and Trap-1. Hsp90 α and β exist in the cytosol and the nucleus in association with a number of other proteins. Hsp90 in its various forms is the most abundant cellular chaperone, and has been shown in experimental systems to be required for ATP-dependent refolding of denatured or “unfolded” proteins. It has therefore been proposed to function as part of the cellular def...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/52
CPCA61K31/52C07D473/40A61P21/00A61P21/02A61P25/00A61P25/14A61P25/16A61P25/28A61P25/36A61P39/02A61P43/00
Inventor CHIOSIS, GABRIELAGREENGARD, PAULDOU, FEILUO, WENJIE
Owner THE ROCKEFELLER UNIV
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